View the Current Issue

Article

  • The EMBO Journal (2002) 21, 4809 - 4819
  • doi:10.1093/emboj/cdf499

Pleiotropic defects in TCR signaling in a Vav-1-null Jurkat T-cell line

Youjia Cao1, Erin M. Janssen2, Andrew W. Duncan1, Amnon Altman3, Daniel D. Billadeau4 and Robert T. Abraham5

  1. Department of Pharmacology and Cancer Biology, Duke University Medical Center, NC 27710, USA
  2. Department of Immunology, Duke University Medical Center, Durham, NC 27710, USA
  3. Division of Cell Biology, La Jolla Institute of Allergy and Immunology, 10355 Science Center Drive, San Diego, CA 92121, USA
  4. Division of Developmental Oncology Research and Department of Immunology, Mayo Clinic, Rochester, MN 55905, USA
  5. Program in Signal Transduction Research, The Burnham Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA

Correspondence to:

Robert T. Abraham, E-mail: abraham@burnham.org

Received 15 April 2002; Accepted 31 July 2002; Revised 23 July 2002

The Rac/Rho-specific guanine nucleotide exchange factor, Vav-1, is a key component of the T-cell antigen receptor (TCR)-linked signaling machinery. Here we have used somatic cell gene-targeting technology to generate a Vav-1-deficient Jurkat T-cell line. The J.Vav1 cell line exhibits dramatic defects in TCR-dependent interleukin (IL)-2 promoter activation, accompanied by significant reductions in the activities of the NFAT(IL-2), NFkappaB, AP-1 and REAP transcription factors that bind to the IL-2 promoter region. In contrast, loss of Vav-1 had variable effects on early TCR-stimulated signaling events. J.Vav1 cells display a selective defect in sustained Ca2+ signaling during TCR stimulation, and complementation of this abnormality by exogenously introduced Vav-1 is dependent on the Vav-1 calponin homology domain. While JNK activation was severely impaired, the stimulation of Ras, ERK and protein kinase C-theta activities, as well as the mobilization of lipid rafts, appeared normal in the J.Vav1 cells. Finally, evidence is presented to suggest that the alternative Vav family members, Vav-2 and Vav-3, are activated during TCR ligation, and partially compensate for the loss of Vav-1 in Jurkat T cells.

  • Keywords:

    • protein kinase C-theta,
    • signal transduction,
    • T-cell antigen receptor,
    • Vav